tbuckley/cabot-search huggingface dataset:
Abstract 1685: Deep learning approaches to deciphering intra-tumoural heterogeneity in glioblastoma
Authors: Anglin J. Dent, Kevin Faust, Brian Lam, Alberto J. Leon, Queenie Tsang, Phedias Diamandis
Journal: Cancer Research (2022)

Abstract BACKGROUND: Emerging evidence strongly implicates intra-tumoral heterogeneous biology in treatment resistance and disease progression across many cancer types. Thus, there is a need for workflows capable of systematically resolving and targeting distinct tumor subpopulations1. Using glioblastoma (GBM) as a prototype, I have aimed to leverage the computational power of Artificial Intelligence (AI) and deep learning to develop an autonomous workflow for the objective definition of biologically distinct tumor subpopulations2. OBJECTIVES: I hypothesize that AI may be leveraged as a tool to resolve spatial heterogeneity, by identifying tumoral subpopulations with unique molecular profiles and therapeutic targets. To highlight the need for routine analysis of tumor heterogeneity, I will address if: METHODS: I apply our developed image clustering workflows to quantify AI-defined subregions within a clinical cohort of 10 GBM patient tumors2,3. Laser capture microdissection and mass spectrometry-based proteomics are leveraged to address if AI-defined subregions show intra-tumoral molecular variation. Further, existing pharmacogenomic databases are utilized to carry out drug sensitivity and transcriptional clustering to define AI-defined region-specific therapeutic sensitivities and resistances across my clinical GBM cohort4. RESULTS: Preliminary data shows that region to region heterogeneity can be found in IDH wild-type GBM using our unbiased omics approach, in addition to predicting different pharmacogenomic sensitivities. CONCLUSIONS: This project aims to develop the first AI-driven tool to guide the routine and systematic molecular analysis of spatial morphogenomic heterogeneity. Further, this tool may have the potential to provide novel approaches for personalized care by selecting drug combinations that target a larger fraction of a tumor’s true biology. 1. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (80-. ). 344, 1396-1401 (2014). 2. Faust, K. et al. Unsupervised Resolution of Histomorphologic Heterogeneity in Renal Cell Carcinoma Using a Brain Tumor-Educated Neural Network. JCO Clin. Cancer Informatics 811-821 (2020) doi:10.1200/cci.20.00035. 3. Roohi, A., Faust, K., Djuric, U. &amp; Diamandis, P. Unsupervised Machine Learning in Pathology: The Next Frontier. Surgical Pathology Clinics vol. 13 349-358 (2020). 4. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity. Nat. 2012 4837391 483, 603-607 (2012). Citation Format: Anglin J. Dent, Kevin Faust, Brian Lam, Alberto J. Leon, Queenie Tsang, Phedias Diamandis. Deep learning approaches to deciphering intra-tumoural heterogeneity in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1685.
Abstract 5570: Development of <i>piggyBac</i> transposon-mediated HER2-CAR-T cells for the treatment of solid tumors
Authors: Koichiro Shioya, Tomio Matsumura, Yuta Ohira, Naomi Komatsuzaki, Manaka Shinagawa, Miyuki Tanaka, Shigeki Yagyu, Yozo Nakazawa, Lilin Zhang
Journal: Cancer Research (2022)

Abstract Background: Although chimeric antigen receptor (CAR)-T therapies have achieved remarkable success in the treatment of hematologic malignancies, the outcome for patients with solid tumors remains poor. There are several reasons behind this, including exhaustion of CAR-T cell, poor homing and penetration in the tumor, and the lack of persistence in the immunosuppressive tumor microenvironment. To solve these problems, we have developed HER2-CAR-T cells (BP2301) using the piggyBac (PB) transposon-based gene transfer system. Methods and Results: Second generation HER2-CAR construct plus PB transposase were introduced into autologous peripheral blood mononuclear cells (PBMC) by electroporation. These cells were activated with UV-inactivated genetically-engineered antigen presenting autologous PBMC (AP cells) expressing HER2, CD80, and 4-1BBL, and propagated for 14 days to obtain the final product (BP2301). BP2301 exhibited dominant fraction of less exhausted stem cell memory-like T cells (Tscm), which could be associated with antitumor efficacy. BP2301 showed robust in vitro killing activity against HER2+ tumor cells even after multiple rounds of cancer cell challenge, suggesting the long-term functionality without immune-exhaustion. In a xenograft murine model of rhabdomyosarcoma cell line (SJCRh30), a single intravenous administration of BP2301 (5 × 106 CAR-positive cells) eradicated the tumor, and mice treated with BP2301 rejected the second tumor establishment owing to the in vivo expansion of BP2301. Conclusion: BP2301 has demonstrated potent anti-tumor activity in vitro and in vivo. We have established a GMP manufacturing process for BP2301, completed non-clinical safety and efficacy studies, and plan to launch an investigator-initiated phase 1 clinical trial to evaluate the safety and efficacy of BP2301 in HER2-expressing sarcoma and gynecologic malignancies in the second quarter of 2022. Citation Format: Koichiro Shioya, Tomio Matsumura, Yuta Ohira, Naomi Komatsuzaki, Manaka Shinagawa, Miyuki Tanaka, Shigeki Yagyu, Yozo Nakazawa, Lilin Zhang. Development of piggyBac transposon-mediated HER2-CAR-T cells for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5570.
Abstract 5726: Splicing-based classifier for gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival
Authors: Yukyung Jun, Yun-Suhk Suh, SungHee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee
Journal: Cancer Research (2022)

Abstract Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer are unknown. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa. We identified and experimentally validated eight splicing events that can classify all gastric cancers into three subtypes: Epithelial-splicing, Mesenchymal-splicing, and Hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in Mesenchymal-splicing and Epithelial-splicing tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, and which is thus readily implementable in the clinic, is sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts Citation Format: Yukyung Jun, Yun-Suhk Suh, SungHee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee. Splicing-based classifier for gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5726.
Abstract 348: Efficacy of triple combination treatment with trametinib, mebendazole and CD133 RNA aptamer in recalcitrant NRAS-mutant melanoma cells
Authors: Yoga Haribabu, Raymond Chien, Ryyan Alobaidi, Li-Wei Kuo, Nusrat Islam, Cynthia M. Simbulan-Rosenthal, Dean S. Rosenthal
Journal: Cancer Research (2022)

Abstract Malignant melanoma is the most aggressive form of skin cancer. Although kinase inhibitors have proven to be efficient with promising clinical results, the development of drug resistance is one of the major issues in targeted therapy. CD133, also known asProminin-1, is a membrane glycoprotein studied extensively as a cell surface marker for cancer stem cells. In our previous studies, mebendazole, a repurposed broad spectrum anti-helminthic agent, inhibited the growth of NRAS mutant melanoma cells in combination with trametinib, a MEK inhibitor. However, a CD133-positive cancer stem cell population remain resistant to this targeted therapy. Use of RNA aptamers in diagnostic as well as therapeutics has been studied recently in different types of cancer cells. Drug delivery of aCD133 aptamer coupled with doxorubicin has been found to inhibit the growth of liver cancer cells. In this study, we targeted the cancer stem cells expressing CD133 with RNA aptamers, in combination with trametinib and mebendazole to sensitize the cells to the combination treatment. Patient derived melanoma cell lines, BAKP and POT, harboring BRAFWT/NRASQ61K and BRAFWT/NRASQ61R driver mutations, were co-transduced with aTet-on vector expressing CD133 and a Tet activator. The doxycycline-induced and uninduced cells were subjected to single agent treatment with 100 nM trametinib, 100 nM mebendazole or 100 nM CD133 RNA aptamer, as well as dual and triple agent combinations for 24 or 48 hours. XTT cell viability and apoptotic assays such as AnnexinV-PI flow cytometry analysis revealed that the triple combination with trametinib, mebendazole and the CD133 aptamer was the most effective in inducing apoptotic cell death, even in the doxycycline-induced CD133-overexpressing melanoma cells. Further studies will use preclinical in vivo mouse xenograft models to investigate the effects on tumor growth of CD133 RNA aptamers in combination treatments, potentially making it available for clinical trials aiming to improve patient response to therapeutics against drug-resistant melanoma cells. Citation Format: Yoga Haribabu, Raymond Chien, Ryyan Alobaidi, Li-Wei Kuo, Nusrat Islam, Cynthia M. Simbulan-Rosenthal, Dean S. Rosenthal. Efficacy of triple combination treatment with trametinib, mebendazole and CD133 RNA aptamer in recalcitrant NRAS-mutant melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 348.
Depression and Anxiety in Patients With Lichen Sclerosus
Authors: Ryan Fan, Audrey C. Leasure, Fahrisa I. Maisha, Alicia J. Little, Jeffrey M. Cohen
Journal: JAMA Dermatology (2022)

This case-control study uses data from the National Institutes of Health All of Us Research Program to investigate whether depression and anxiety are associated with lichen sclerosus among women.
Abstract 5141: Using single cell gene expression to develop treatment response predictions in multiple myeloma
Authors: Jonathan Scolnick, Stacy Xu, Sanjay de Mel, Cinnie Yentia Soekojo, Wee Joo Chng
Journal: Cancer Research (2022)

Abstract The promise of precision medicine in oncology is to identify the ideal treatment for each patient, eliminating failed treatment cycles and reducing treatment burdens on patients and payors. While gene sequencing can predict effective treatment options in some cases, studies have estimated that only 10-15% of cancer patients are treated with genotype matched drugs. Additional treatment selection tools for predicting patient response thus remains a critical clinical need. While gene sequencing has clear utility in predicting therapeutic response, gene expression is less commonly used in clinical tests to guide treatment selection. Gene expression is theoretically attractive to predicting therapeutic response because, unlike mutational analysis, it provides a direct readout of the dysregulated biochemical activities in the cells which may be targeted by particular therapies. One of the major problems with conventional approaches to using gene expression to predict therapeutic response is tumor heterogeneity; that is, a biopsied tumor contains multiple cells types and even different tumor clones that can confound a conventional bulk gene expression analysis. More recently, single-cell RNA expression analysis technologies have grown in popularity. These technologies enable the fine characterization of tumors and their cellular makeup and hold the promise of increasing the power of gene expression measurements for identifying therapy response prediction tools. Here we show the application of single cell gene expression analysis with Proteona’s MapResponse™ machine-learning algorithms to developing a predictive classifier for patient response to Daratumumab treatment in multiple myeloma. Starting with publicly available data (Cohen et al. Nat. Medicine 2021), we developed a classifier that accurately predicted the response of 94% of subjects in the published study. This classifier was able to accurately predict response in an independent cohort of Daratumumab-treated patients. In contrast, the classifier performed poorly in a cohort of patients who did not receive Daratumumab. Together these data suggest the classifier has specificity to predicting response to Daratumumab and is not a general prognostic signature. These early findings point to the potential value of combining single-cell RNA sequencing with machine-learning methods such as MapResponse™ to bring precision medicine to more patients. Citation Format: Jonathan Scolnick, Stacy Xu, Sanjay de Mel, Cinnie Yentia Soekojo, Wee Joo Chng. Using single cell gene expression to develop treatment response predictions in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5141.
Abstract 5596: TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival
Authors: Nanmeng Yu, George J. Weiner
Journal: Cancer Research (2022)

Abstract Background: Rituximab is a central component of chemoimmunotherapy for B cell lymphomas. With over two decades in clinical use, new insights into its mechanisms of action continue to emerge. Rituximab infusion into patients results in elevated levels of TNFα in patient sera. However, our understanding of the mechanism of TNFα production in the context of rituximab and its role in anti-tumor immunity remain limited. In our study, we sought to determine the major producers of TNFα following rituximab treatment and the effect of rituximab-induced TNFα on anti-tumor effector cells. Methods: Peripheral blood mononuclear cells (PBMCs) from normal donors were cocultured in vitro with CD20-expressing Raji cells for 1 to 7 days. The coculture was treated with rituximab or non-specific antibody trastuzumab. Recombinant TNFα or TNFα blocking antibody infliximab were used to test the effect of TNFα in the rituximab- or trastuzumab-treated coculture system. ELISA was used to evaluate TNFα production in culture supernatant. Multicolor flow cytometry was used to evaluate for phenotypic and functional changes with TNFα treatment or blockade in various immune cell populations. Results: TNFα was robustly produced by PBMCs when treated with rituximab. This production was mediated by the Fc portion of rituximab antibody, as rituximab Fab elicited very little if any TNFα response from PBMCs. Myeloid dendritic cells (HLA-DR+CD123-CD11c+) were the key producers of TNFα in response to rituximab. In the absence of antibody therapy, recombinant TNFα treatment induced proliferation and survival of two major effector cells in the peripheral blood: monocytes and NK cells as determined by cell count and percent of Ki67+ cells. TNFα blockade using infliximab inhibited monocyte and NK cell proliferation and survival. TNFα blockade also protected Raji cells from rituximab-mediated killing. Conclusions: Rituximab-induced TNFα production promotes the proliferation and survival of monocytes and NK cells. Myeloid dendritic cells are necessary for TNFα production in this context. These results highlight the complexity of the immune response to rituximab treatment. Additional studies are ongoing exploring the role TNFa plays in the therapeutic response to rituximab. Citation Format: Nanmeng Yu, George J. Weiner. TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5596.
Abstract 1384: Immunopeptidome analysis of mouse MHC Class I
Authors: Seeta Nyayapathy, Richard Jones, Michael Ford, Michael Pisano, Julie M. Rumble
Journal: Cancer Research (2022)

Abstract MHC class I is required for antigen presentation to CD8 T cells. These cell-surface proteins are heterodimers consisting of a variable alpha chain associated with β2 microglobulin and are expressed on nucleated cells at varying levels. The antigen specificity of the interaction between MHC, peptide and T cell receptor can be exploited in development of personalized cancer vaccines and other immunotherapies against cancer. MHC sequences are species-specific and there are many different haplotypes of MHC class I. For this reason, the antibodies used for immunoprecipitation of MHC complexes are a critical component of the workflow for identification of antigens presented by MHC. Subclasses of mouse MHC class I are divided into classical (H-2D, H-2K and H-2L) and non-classical (H-2Q, H-2M and H-2T), and haplotypes of each are known for homozygous inbred laboratory strains of mice. One common strain is C57BL/6, which expresses H2-Db and H2-Kb classical MHC molecules. Antibody clone M1/42, which reacts with H-2 expressed on nucleated cells from mice of a, b, d, j, k, s and u haplotypes, is commonly referred to as a pan-MHC class I antibody. Antibody clones Y-3 and HB-27 recognize H2-Kb and H2-Db haplotypes, respectively. In this study we aimed to compare different antibodies to mouse MHC class I complexes for their efficiency of recovery of associated peptides. Input was murine EL-4 cells which are T lymphoblast cells derived from a C57BL/6 background. We performed immunoprecipitation with different antibodies either singly or sequentially to enrich MHC class I, followed by gentle elution of associated peptides and finally peptide analysis by mass spectrometry. Each immunoprecipitation workflow yielded a different (but overlapping) cohort of peptides, suggesting optimal methodologies for analyses of immunopeptidomes from common laboratory mouse strains. Citation Format: Seeta Nyayapathy, Richard Jones, Michael Ford, Michael Pisano, Julie M. Rumble. Immunopeptidome analysis of mouse MHC Class I [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1384.
Abstract 1326: Loss of p53 sensitizes tumor cells to immune checkpoint blockade therapy via upregulation of IL-33
Authors: David Shihong Gao, Yang Li, Jason Shoush, Runzi Sun, Binfeng Lu
Journal: Cancer Research (2022)

Abstract Recent studies suggest p53 contributes to poor survival in the context of immune checkpoint blockade (ICB). Mutations to p53 significantly improve the response rate to PD-1 ICB in lung cancer patients. Tumor-derived IL-33 is required for the anti-tumor immune response and efficacy of ICB. However, the relationship between p53 and IL-33 during ICB is unknown. In this study, we characterize the role of the p53/IL-33 axis in regulating the response of the tumor microenvironment to ICB. We use CRISPR-Cas9 to delete Trp53 from murine MC38 colon adenocarcinoma. Deletion of Trp53 and PD-1 ICB synergistically inhibits tumor growth. Il33 is upregulated in the Trp53-deficient and treated tumor cells, and its expression increases with time and response to treatment. Cd4+ and Cd8+ T cell infiltration increases adjacent to IL-33 expressing tumor cells, while Treg infiltration is decreased. Simultaneous deletion of Il33 in MC38 tumors reverses the efficacy PD-1 ICB. Trp53-deficient MC38 in ST2-/- (IL-33 receptor) mice also show no response to PD-1 ICB. Our findings depict a novel mechanism by which the loss of p53 in tumors treated with ICB unleashes the expression of tumoral IL-33 and induces downstream signaling. p53 mutations may be a double-edged sword for cancer, i.e. the loss of the tumor suppressor initially facilitates tumorigenesis, but eventual buildup of mutations and activation of damage pathways, such as NF-kB, leads to upregulation of danger signals in the tumor. These danger signals, such as IL-33, mediate the anti-tumor effect of ICB. Citation Format: David Shihong Gao, Yang Li, Jason Shoush, Runzi Sun, Binfeng Lu. Loss of p53 sensitizes tumor cells to immune checkpoint blockade therapy via upregulation of IL-33 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1326.
Abstract 407: OTS964, a TOPK inhibitor, is susceptible to ABCG2-mediated drug resistance
Authors: Yuqi Yang, Zhuo-Xun Wu, Jing-Quan Wang, Qiu-Xu Teng, Zi-Ning Lei, Sabrina Lusvarghi, Suresh V. Ambudkar, Ning Ji, Zhe-Sheng Chen
Journal: Cancer Research (2022)

Abstract The overexpression of ATP-binding cassette (ABC) transporters has known to be one of the most important mechanisms responsible for the development of multidrug resistance (MDR). OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and MDR-associated ATP-binding cassette sub-family G member 2 (ABCG2, breast cancer resistance protein/BCRP). The cell viability assay indicated that the effectiveness of OTS964 is limited in drug-resistant and gene-transfected cells overexpressing ABCG2. We found that the known ABCG2 inhibitor is able to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein and mRNA expression levels, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner, and that this stimulation can be antagonized by a verified ABCG2 ATPase inhibitor. Additionally, the computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 protein and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells. Citation Format: Yuqi Yang, Zhuo-Xun Wu, Jing-Quan Wang, Qiu-Xu Teng, Zi-Ning Lei, Sabrina Lusvarghi, Suresh V. Ambudkar, Ning Ji, Zhe-Sheng Chen. OTS964, a TOPK inhibitor, is susceptible to ABCG2-mediated drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 407.